Intermediates and processes for the synthesis of Ramelteon

ABSTRACT

Provided are intermediates and processes for preparation of Ramelteon.

CROSS REFERENCE

The Present application claims benefit of U.S. provisional ApplicationNo. 60/903,782, filed Feb. 26, 2007, whose entire disclosure isincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to synthesis of (S)—N-[2-(1, 6, 7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide i.e.Ramelteon.

BACKGROUND OF THE INVENTION

ROZEREM® (Ramelteon) is a melatonin receptor agonist with both highaffinity for melatonin MT1 and MT2 receptors and selectivity over theMT3 receptor. The empirical formula for Ramelteon is C₁₆H₂₁NO₂, and itsmolecular weight is 259.34. Ramelteon is freely soluble in methanol,ethanol, dimethylsulfoxide (DMSO), 1-octanol and is highly soluble inwater and aq. buffer. Ramelteon has the following chemical structure:

Ramelteon is the active ingredient and sold under the brand name ofROZEREM®. Ramelteon is approved by the United States Food and DrugAdministration for the treatment of insomnia characterized by difficultywith sleep onset.

Different processes for preparing(S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamidei.e. Ramelteon are disclosed in U.S. Pat. No. 6,034,239, JP 11080106, JP11140073 and WO 2006/030739.

U.S. Pat. No. 6,034,239 discloses the following processes for thepreparation of Ramelteon:

Japan Patent Publication No. 11080106 discloses the following processesfor the preparation of Ramelteon:

Japan Patent Publication No. 11140073 discloses the following processesfor the preparation of an intermediate of Ramelteon:

PCT Publication No. 2006/030739 discloses the following processes forthe preparation of an intermediate of Ramelteon:

The present invention provides additional processes for preparationRamelteon and intermediates thereof.

SUMMARY OF INVENTION

In one embodiment, the present invention provides a process forproducing Ramelteon intermediate of formula IV, comprising the step of:combining the compound of Formula II with compound of formula III in thepresence of base and organic solvent:

Wherein

X=O-Alkyl or —NH₂. In one embodiment X is ethoxy.

In one embodiment, the present invention encompasses a process forpreparing Ramelteon, by preparing the compound of Formula IV asdescribed above, and converting it to Ramelteon.

In another embodiment, the present invention encompasses a process forpreparing a Ramelteon intermediate of formula V, comprising chiralreduction of compound of formula IV in presence of Ru-BINAP complexunder hydrogen atmosphere in an organic solvent:

Wherein

X=O-Alkyl or —NH₂. In one embodiment X is ethoxy.

In one embodiment, the present invention encompasses a process forpreparing Ramelteon, by preparing the compound of Formula V as describedabove, and converting it to Ramelteon.

In another embodiment, the present invention encompasses a process forpreparing a Ramelteon intermediate of formula VI, comprising reactingthe compound of formula V with brominating agent in presence of an acidor alkaline salt of an acid:

Wherein

X=O-Alkyl or —NH₂. In one embodiment X is ethoxy.

In one embodiment, the present invention encompasses a process forpreparing Ramelteon, by preparing the compound of Formula VI asdescribed above, and converting it to Ramelteon.

In another embodiment, the present invention encompasses a process forpreparing a Ramelteon intermediate of formula VII, comprising removingthe protective group for the hydroxyl group in compound of formula VI:

Wherein X=O-Alkyl or —NH₂. In one embodiment X is ethoxy.

The deprotection of hydroxyl group can be carried out by a reagentselected from the group comprising of boron tribromide (BBr₃),hydrobromic acid (HBr) in acetic acid, pyridine-HBr, quarternaryammonium salt, 2-(diethylamino) ethanethial.HCl, trifluoroacetic acid,anisole and aluminum trichloride (AlCl₃). The reaction is conducted in asolvent, for example, halogenated hydrocarbons, a C₆ to C₁₄ aromatichydrocarbon, a C₁ to C₇ aliphatic hydrocarbon, a C₁ to C₅ alcohol, a C₂to C₇ ester, and a C₂ to C₇ ether, a C₁ to C₇ organic acid, inorganicacid or a suitable mixture thereof.

In one embodiment, the present invention encompasses a process forpreparing Ramelteon, by preparing the compound of formula VII asdescribed above, and converting it to Ramelteon.

In another embodiment, the present invention encompasses a process forpreparing the Ramelteon intermediate of formula IX, comprising reactingthe compound formula VII with the compound of formula VIII in presenceof a base to produce the compound of formula IX:

Wherein X=O-Alkyl or —NH₂. In one embodiment X is ethoxy.

In one embodiment, the present invention encompasses a process forpreparing Ramelteon, by preparing the compound of formula IX asdescribed above, and converting it to Ramelteon.

In another embodiment, the present invention encompasses a process forpreparing the Ramelteon intermediate of formula X, cyclizing thecompound of formula IX to produce compound of formula X:

Wherein X=O-Alkyl or —NH₂. In one embodiment X is ethoxy.

In one embodiment, the present invention encompasses a process forpreparing Ramelteon, by preparing the compound of Formula X as describedabove, and converting it to Ramelteon.

In another embodiment, the present invention encompasses a process forpreparing the Ramelteon intermediate of formula XI, comprisingde-bromination of compound of formula X by reduction:

Wherein X=O-Alkyl or —NH₂. In one embodiment X is ethoxy.

In one embodiment, the present invention encompasses a process forpreparing Ramelteon, by preparing the compound of Formula XI asdescribed above, and converting it to Ramelteon.

In another embodiment, the present invention encompasses a process forpreparing the Ramelteon intermediate of formula XII, comprising reactingthe compound of formula XI with an aminating agent:

Wherein X=O-Alkyl or —NH₂. In one embodiment X is ethoxy.

In one embodiment, the present invention encompasses a process forpreparing Ramelteon, by preparing the compound of Formula XII asdescribed above, and converting it to Ramelteon.

In another embodiment, the present invention encompasses a process forpreparing a Ramelteon intermediate of formula XIII, comprising reductionof compound of formula XII with a reducing agent:

In another embodiment, the present invention encompasses a process forpreparing Ramelteon of formula I, comprising reacting compound offormula XIII with propionyl chloride and base to produce Ramelteon offormula I.

In another embodiment, the present invention encompasses a process forpreparing Ramelteon (with mild conditions) of Formula I comprising:

-   (a) reacting the compound of formula II with compound of formula III    in presence of an inorganic base and an organic solvent:

-   (b) chiral reduction of compound of formula IV to obtain compound of    formula V:

-   (c) combining compound of formula V with brominating agent in    presence of an acid or alkaline salt of an acid:

-   (d) demethylation of the compound of formula VI to obtain the    compound of formula VII in the presence of demethylating reagent    such as BBr3, HBr in acetic acid, pyridine-HBr, quarternary ammonium    salt, 2-(diethylamino) ethanethiol.HCl, trifluoroacetic acid,    anisole and AlCl₃ and an organic solvent:

-   (e) combining the compound of formula VII with compound of formula    VIII in presence of base to produce the compound of formula IX:

-   (f) cyclizing the compound of formula IX in presence of methane    sulfonic acid, trifluoroacetic acid, p-toluene sulphonic acid to    obtain the compound of formula X:

-   (g) debrominating the compound formula X by reacting the compound of    formula X with dehalogenation reaction to produce the compound of    formula XI:

-   (h) combining the compound of formula XI with an aminating agent to    obtain the compound of formula XII:

-   (i) reducing the compound formula XII with, boron trihalide complex,    and sodium borohydride to produce the compound of formula XIII:

-   (j) combining the compound of formula XIII with propionyl chloride    and base to produce Ramelteon of formula I:

Wherein X=O-Alkyl or —NH₂. In one embodiment X is ethoxy.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term ‘alkyl’ refers to a straight or branchedhydrocarbon chain radical consisting of carbon and hydrogen atoms,containing no unsaturation, having from one to eight carbon atoms, andwhich is attached to the rest of the molecule by a single bond, e.g.,methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), and the like.

As used herein, the term “aryl” refers to aromatic radicals having inthe range of 6 up to 14 carbon atoms such as phenyl, substituted phenyl,naphthyl, tetrahydronapthyl, indanyl, biphenyl and the like.

As used herein, the term “arylalkyl” refers to an aryl group as definedabove directly bonded to an alkyl group as defined above. e. g.,—CH₂C₆H₅, —C₂H₄C₆H₅ and the like.

As used herein, the term “alkoxy” denotes alkyl group as defined aboveattached via oxygen linkage to the rest of the molecule. Representativeexamples of those groups are —OCH₃, —OC₂H₅ and the like.

As used herein, the term “alkoxycarbonyl” denotes —C(O)— is linked toalkoxy group such —C(O)OCH₃, —C(O)OC₂H₅ etc. The term “alkoxy” isdefined as above.

As used herein, the term “cycloalkyl” denotes a non-aromatic mono ormulticyclic ring system of about 3 to 12 carbon atoms such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and examples ofmulticyclic cycloalkyl groups include perhydronapththyl, adamantyl andnorbornyl groups bridged cyclic group or sprirobicyclic groups e.g.sprio (4,4) non-2-yl.

The substituents in the ‘substituted alkyl’, ‘substituted aryl,‘substituted arylalkyl’ and substituted alkoxycarbonyl and may be thesame or different which one or more selected from the groups such ashydrogen, hydroxy, carboxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstituted aryl,substituted or unsubstituted arylalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted amino;

The term “amine” refers to —NH₂.

The substituents in the ‘substituted alkyl’, ‘substituted aryl,‘substituted arylalkyl’ and substituted alkoxycarbonyl and may be thesame or different which one or more selected from the groups such ashydrogen, hydroxy, carboxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstituted aryl,substituted or unsubstituted arylalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted amino.

As used herein, aqueous ammonia refers to 5-35% aqueous ammonia.

As used herein, the term “halogenated hydrocarbons” refers to cyclic oracyclic, saturated or unsaturated aliphatic or aromatic hydrocarbons.Examples of halogenated hydrocarbons include, but are not limited to,halogenated alkanes such as chloromethane, dichloromethane,chloroethane, dichlorotrifluoroethane, difluoroethane, hexachloroethane,pentafluoroethane, halogenated alkenes such as such astetrachloroethene, dichloroethene, trichloroethene, vinyl chloride,chloro-1,3-butadiene, chlorotrifluoroethylene, or halogenated benzenessuch as benzotrichloride, benzyl chloride, bromobenzene, chlorobenzene,chlorotoluene, dichlorobenzene, fluorobenzene, or trichlorobenzene. Thepreferred halogen is chlorine. The preferred halogenated hydrocarbonsare aromatic hydrocarbons or C1-C4 alkanes, and more preferablychlorinated aromatic hydrocarbons or C1-C4 alkanes. The more preferredhalogenated hydrocarbons are chlorobenzene, o- or p-dichlorobenzene,dichloromethane, or o-chlorotoluene.

In one embodiment, the present invention provides a process forproducing Ramelteon intermediate of formula IV, comprising the step of:combining the compound of formula II with compound of formula III in thepresence of a base and an organic solvent:

Wherein X=O-Alkyl or —NH₂. In one embodiment X is ethoxy.

Suitable bases include alkali metal carbonates, hydroxides or hydrides,for example potassium bicarbonate, sodium bicarbonate, potassiumcarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide,sodium hydride, and potassium hydride; organic bases of the structureNR₃ wherein R is an organic radical of 1-5 carbons, like triethyl amine,diisopropyl ethyl amine, N-methyl morpholine; metal amides, for example,sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide,metal alkoxides, for example, sodium methoxide, sodium ethoxidepotassium tert-butoxide, etc. n-butyl lithium (n-BuLi); 1,8-diazabicyclo(5.4.0) undec-7-ene; hexamethylphosphoramide. Sodium hydride (NaH) is apreferred base for use in the practice of the present invention.

Suitable organic solvents can be selected from the group consisting ofC₆₋₁₀ substituted aromatic hydrocarbons, C₁₋₅ aliphatic hydrocarbons,halogenated hydrocarbons, ethers, ketones, esters, nitrites, C₄₋₆straight, branched or cyclic hydrocarbons, dioxanes, DMF, DMSO, andmixtures thereof. A preferred C₆₋₁₀ substituted aromatic hydrocarbon iseither toluene or xylene. The ethers, ketones, esters may be C₂ to C₇. Apreferred nitrile is acetonitrile.

The compound of Formula IV can then be used to prepare Ramelteon.

In another embodiment, the present invention encompasses a process forpreparing a Ramelteon intermediate of formula V, comprising chiralreduction of compound of formula IV in presence Ru-BINAP complex such asRu₂Cl₄[(R)-BINAP]₂NEt₃, Ru₂[(R)-BINAP](OAc), Ru(OAc)₂[(R)-T-BINAP],Ru₂Cl₄[(R)-DM-BINAP]₂NEt₃, Ru₂[(R)-T-BINAP](OAc),[RuCl(Benzene)((R)-BINAP)]Cl, [RuCl(p-Cymene)((R)-BINAP)]Cl,[RuBr(p-Cymene)((R)-BINAP)]Br, [RuI(p-Cymene)((R)-BINAP)]I underhydrogen atmosphere in an organic solvent selected from the groupconsisting of: a C₆ to C₁₄ aromatic hydrocarbon, C₁ to C₅ alcohol, a C₂to C₇ ester, and a C₂ to C₇ ether, halogenated hydrocarbons or asuitable mixture thereof. Preferable organic solvents are methanol,ethanol, isopropanol (IPA), ethyl acetate, dither ether, diisopropylether, dichloromethane, dichloroethane, toluene and xylene. Mostpreferable solvent is selected from methanol, ethanol and toluene. Thehydrogen atmosphere can have a pressure of about 3 to about 5 bar.

Wherein X=O-Alkyl or —NH₂. In one embodiment X is ethoxy.

The compound of Formula V can then be used to prepare Ramelteon.

In another embodiment, the present invention encompasses a process forpreparing the Ramelteon intermediate of formula VI, comprising: reactingthe compound of formula V with brominating agent in presence of an acidor an alkaline salt of organic acid or an acid acceptor. The process canbe carried out in an organic solvent selected from the group consistingof: a C₆ to C₁₄ aromatic hydrocarbon, a C₁ to C₅ aliphatic hydrocarbon,a C₁ to C₅ alcohol, a C₂ to C₇ ester, and a C₂ to C₇ ether, a C₁-C₇acid, halogenated hydrocarbons, C₁-C₅ organic acid or a suitable mixturethereof. Preferable solvents are dichloromethane, ethyl acetate,acetonitrile, methanol and acetic acid. Most preferable solvent ismethanol or acetic acid. The brominating agent can be used in an amountof 0.2 to 2 moles on the basis of 1 mole of the compound having astructure of chemical formula V.

Wherein X=O-Alkyl, or —NH₂

The brominating agent can be Br₂ or liquid bromine. The acid can includeorganic or inorganic acid. Preferably, the organic acid is selected fromacetic acid, formic acid, methane sulfonic acid, benzoic acid; inorganicacids include hydrochloric acid, hydrobromic acid, phosphoric acid; analkaline salt of organic acid is selected from Sodium acetate potassiumacetate, sodium format. Alkaline salt of organic acid can be selectedfrom the group consisting of sodium acetate, sodium formate, sodiumphosphate, potassium acetate, potassium formate and potassium phosphate.

The compound of Formula VI can then be used to prepare Ramelteon.

In another embodiment, the present invention encompasses a process forpreparing the Ramelteon intermediate of formula VII, comprising removingthe protective group for the hydroxyl group in compound of formula VI.

Wherein X=O-Alkyl or —NH₂. In one embodiment X is ethoxy.The deprotection can be carried out by using reagents such as BBr₃, HBrin acetic acid, pyridine-HBr, quarternary ammonium salt,2-(diethylamino)-ethanethiol.HCl, trifluoroacetic acid, anisole andAlCl₃. Suitable solvents include halogenated hydrocarbons, a C₆ to C₁₄aromatic hydrocarbon, a C₁ to C₇ aliphatic hydrocarbon, a C₁ to C₅alcohol, a C₂ to C₇ ester, and a C₂ to C₇ ether, a C₁ to C₇ organicacid, inorganic acid or a suitable mixture of these solvents. Mostpreferable solvent is dichloromethane.

The compound of Formula VII can then be used to prepare Ramelteon.

In another embodiment, the present invention encompasses a process forpreparing the Ramelteon intermediate of formula IX, comprising reactingthe compound formula VII with the compound of formula VIII in presenceof a base to produce the compound of formula IX at a temperature of25-40° C. under nitrogen atmosphere. The condensation reaction furthercomprises adding an organic solvent. The obtained reaction mixture canbe stirred at a temperature of 30-60° C. for 5-8 hr. Typically, themolar amount of compound of formula VIII is 1 to 2 times the molaramount of the compound of formula VII; the molar amount of base will be1 to 4 times the molar amount of the compound of formula VII;

Wherein X=O-Alkyl or —NH₂. In one embodiment X is ethoxy.

The base can be selected from alkali metal carbonates, hydroxides orhydrides, for example potassium bicarbonate, sodium bicarbonate,potassium carbonate, sodium carbonate, sodium hydroxide, potassiumhydroxide, sodium hydride, potassium hydride; organic bases liketriethylamine (TEA), diethylamine (DEA); metal amides, for example,sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide,etc., metal alkoxides, for example, sodium methoxide, sodium ethoxidepotassium tert-butoxide, etc. n-BuLi; 1,8-Diazabicyclo (5.4.0)undec-7-ene; hexamethylphosphoramide etc. potassium hydroxide, andpotassium tert-butoxide are preferred bases for use in the practice ofthe present invention. The organic solvent can be selected from thegroup consisting of halogenated hydrocarbons, C₆ to C₁₄ aromatichydrocarbon, C₁ to C₇ aliphatic hydrocarbon, C₁ to C₅ alcohol, C₂ to C₇ester, C₂ to C₇ ether, DMSO, DMF and mixtures thereof. Preferableorganic solvents are isopropyl alcohol, acetone, DMF, DMSO, THF. Mostpreferable organic solvent is selected from isopropyl alcohol, acetone,and DMF.

The compound of Formula IX can then be used to prepare Ramelteon.

In another embodiment, the present invention encompasses a process forpreparing the Ramelteon intermediate of formula X, cyclizing thecompound of formula IX to produce compound of formula X. Cyclization canbe conducted by, for example, heating the compound, using an acidicsubstance or a basic substance.

Wherein X=O-Alkyl or —NH₂. In one embodiment X is ethoxy.

The cyclization under heating is conducted in either the absence of asolvent or the presence of a solvent inert to the reaction. Solventsused in this reaction include high-boiling point hydrocarbons such as1,2,3,4-tetrahydronaphthalen, bromobenzene etc.; high boiling pointethers such as diphenyl ether, dimethyleneglycol dimethyl ether etc.,N,N-dimethylaniline, N,N-diethylaniline etc., or a suitable mixture ofthese solvents are preferable. The reaction is conducted at atemperature of about 0° C. to about 250° C.; preferably 10-90° C. Thereaction time is generally 1 hr to 10 hr; preferably 1 hr to 8 hr andmost preferably 6 to 8 hr.

The cyclization under acidic conditions uses the acidic substances suchas phosphous oxychloride, phosphorus pentoxide, thionyl chloride,hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid,polyphosphoric acid, p-toluenesulfonic acid, methane sulphonic acid,trihaloacetic acid; preferably methane sulfonic acid, trifluoroaceticacid, p-toluene sulphonic acid. Typically, the molar amount of acidicsubstance is 0.3 to 10 times the molar amount of the compound of formulaIX; preferably 0.3 to 2 times. The reaction may be conducted in asolvent inert to the reaction or without a solvent. The reactiontemperature is generally 10-150° C., preferably 10 to 50° C. Thesolvents of the reaction include C₆₋₁₂ aromatic hydrocarbons, C₄₋₇saturated hydrocarbons, ethers such as tetrahydrofuran, dioxane,1,2-dimethoxyethane; amides such as N,N-dimethylformamide,N,N-dimethylacetamide; halogenated hydrocarbons such as dichloromethane,dichloroethane, chloroform, carbon tetrachloride; anhydrides such asacetic anhydride; sulfoxides, such as dimethylsulfoxide; water; ormixture thereof. The reaction time is generally 1 hr to 9 hr, preferably2 hr to 8 hr.

In the case where the cyclization is conducted by using a basicsubstance, the basic substance includes, for example, sodium hydroxide,potassium hydroxide, sodium carbonate, potassium carbonate, sodiumhydrogencarbonate. The basic substance is used in an amount ofapproximately 0.4 to 10 moles, preferably approximately 5.0 to 20 molesper mol of compound formula VIII. The reaction may be conducted in asolvent inert to the reaction or without a solvent. The solvent of thereaction includes alcohols such as methanol, ethanol, propanol, etc.;ketones such as acetone, methyl ethyl ketone; water; or a suitablemixture of these solvents. The reaction time is generally 30 minutes to10 hours, preferably 30 minutes to 6 hours. The reaction temperature isgenerally 20-150° C.; preferably 20 to 100° C.

The compound of Formula X can then be used to prepare Ramelteon.

In another embodiment, the present invention encompasses a process forpreparing the Ramelteon intermediate of formula XI, comprisingdehalogenating the compound of formula X by using metal hydrides such asNaBH₄ or LiLH₄, or catalytic reduction in presence of Pd—C, Raney-Ni,Zn/HCl, Fe/HCl, hydrogen atmosphere 0.1 kg to 100 kg pressure,preferably 5-10 kg pressure. The preferable reduction catalysts arePd—C, Raney-Nickel, Zn/HCl and Fe/HCl. The reaction is conducted in asolvent selected from the group comprising of halogenated hydrocarbons,a C₆ to C₁₄ aromatic hydrocarbon, a C₁ to C₅ alcohol, a C₂ to C₇ ester,and a C₂ to C₇ ether, a C₁ to C₅ carboxylic acid, water, or a suitablemixture of these solvents; preferably methanol, isopropyl alcohol,dichloromethane, toluene, ethyl acetate, diethyl ether. The reactiontemperature is generally 15-100° C., preferably 20-40° C. The reactiontime is generally 1 hr to 8 hrs, preferably 2 hrs to 4 hrs. Typically,the amount of catalyst used is 2-30 g per 100 g of the compound offormula X; preferably 5-20 g per 100 g of the compound of formula X.

Wherein X=O-Alkyl or —NH₂. In one embodiment X is ethoxy.

The compound of Formula XI can then be used to prepare Ramelteon.

In another embodiment, the present invention encompasses a process forpreparing a Ramelteon intermediate of formula XII, comprising reactionof compound of formula XI with aqueous ammonia, or ammonia in any form,preferably in amounts ranging from 1 to 50 moles relative to compound offormula X, more preferably 2-20 moles. The reaction is carried out inthe presence of a solvent selected from halogenated hydrocarbons, C₆ toC₁₄ aromatic hydrocarbon, C₁ to C₅ alcohol, C₂ to C₇ ester, and C₂ to C₇ether or mixtures thereof. Preferably the solvent is methanol,isopropanol, ethyl acetate, dichloromethane, in amounts ranging from 1to 5 volumes relative to compound of formula XI at a temperature rangingfrom 20 to 150° C., preferably from 20 to 50° C. The reaction time isusually about 1 hr to about 10 hr; preferably about 3 hr to about 6 hr.

Wherein X=O-Alkyl or —NH₂. In one embodiment X is ethoxy.

The compound of Formula XII can then be used to prepare Ramelteon.

In another embodiment, the present invention encompasses a process forpreparing the Ramelteon intermediate of formula XIII, as described byToru Yamano et al, Tetrahedron: Asymmetry 17 (2006) 184-190 & JP11080106; which comprising reduction of compound of formula XII byadding boron-trifluoride diethyl ether complex and tetrahydrofuran tosodium borohydride at −10° C. The mixture is stirred at room temperaturefor 1 hr. After cooling to 0° C., compound of formula XII is added andstir at room temperature for 24 hr.

The compound of Formula XIII can then be used to prepare Ramelteon.

In another embodiment, the present invention encompasses a process forpreparing Ramelteon of formula I, as described by Toru Yamano et al, JP11080106; which comprising reacting compound of formula XIII withpropionyl chloride in presence of triethyl amine and tetrahydrofuran assolvent.

The above steps can be combined to obtain a continuous process startingfrom intermediates II and III, and ending in compound I. Alternatively,one of ordinarily skill of art could utilize only select steps of thisprocess and combine these steps with other methods. This process, whenutilizing all of the steps, comprises preparing Ramelteon, having theFormula I

Comprising

-   (a) reacting the compound of formula II with compound of formula III    in presence of base and an organic solvent;

-   (b) chiral reduction of compound of formula IV in presence Ru-BINAP    complex;

-   (c) reacting the compound of formula V with brominating agent in    presence of an acid or an alkaline salt of organic acid or any acid    acceptor;

-   (d) removing the protective group for the hydroxyl group in compound    of formula VI;

-   (e) reacting the compound formula VII with the compound of formula    VIII in presence of a base to produce the compound of formula IX;

-   (f) cyclizing the cyclizing the compound of formula IX to produce    compound of formula X;

-   (g) dehalogenating the compound of formula X to obtain compound of    formula XI;

-   (h) reacting compound of formula XI with aqueous ammonia, or ammonia    to obtain compound XII;

-   (i) reducing the compound of formula XII to obtain the compound of    formula XIII;

-   (j) converting compound XIII to compound I;

Wherein X=O-Alkyl or —NH₂. In one embodiment X is ethoxy. Detailedconditions for each of these steps (a-j) are provided above.

The present invention provides a compound having the followingstructure:

In one embodiment compound IV has the S isomeric structure. Compound IVcan be obtained as a product by reacting compounds II and III asdescribed above. After formation of compound IV, water can be added tothe reaction

Compound IV

mixture to obtain two phases, particularly if the reaction is carriedout with a water immiscible solvent. The organic layer can be washed.The product can be recovered from the organic layer, such by applying apressure of less than one atmosphere and/or a heated temperature ofabout 40 to about 60° C. The product may be purified by HPLC. Theproduct may be purified to obtain a purity of about 50% to about 98%,such as of about 95% to about 98%, as measured by area percentage HPLC.The present invention provides a compound having the followingstructure:

In one embodiment compound V has the S isomeric structure. Compound Vcan be obtained from compound IV as described above. The reactionmixture can be filtered to remove impurities. Compound V can berecovered from the reaction mixture by evaporating the reaction mixture,such as by applying a pressure of less than one atmosphere and/or aheated temperature of about 40 to about 60° C. The product may bepurified to obtain a purity of about 50% to about 98%, such as of about95% to about 98%, as measured by area percentage HPLC.

The present invention provides a compound having the followingstructure:

In one embodiment compound VI has the S isomeric structure. Compound VIcan be prepared from compound V as described above. It can be recoveredfrom the reaction mixture. During the reaction, the mixture can bestirred to accelerate the reaction between compounds IV and V. CompoundVI can be recovered from the organic layer by evaporation, such as byapplying a pressure of less than one atmosphere and/or a heatedtemperature of about 40 to about 60° C. The product may be purified toobtain a purity of about 50% to about 95%, such as of about 90% to about95%, as measured by area percentage HPLC.

The present invention provides a compound having the followingstructure:

In one embodiment compound VII has the S isomeric structure. CompoundVII can be prepared from compound VI as described above. Aftercompletion of the reaction, water can be combined with the reactionmixture, to obtain two phases, particularly if the reaction is carriedout in a water immiscible solvent. It can be recovered by evaporatingthe reaction mixture, such as by applying a pressure of less than oneatmosphere and/or a heated temperature of about 40 to about 60° C. Theproduct can may purified to obtain a purity of about 50% to about 95%,such as of about 90% to about 95%, as measured by area percentage HPLC.

The present invention provides a compound having the followingstructure:

In one embodiment compound IX has the S isomeric structure. Compound IXcan be prepared by reacting compounds VIII and VII as described above.After completion of the reaction, water can be combined with thereaction mixture, to obtain two phases, particularly if the reaction iscarried out in a water immiscible solvent. It can be recovered byevaporating the reaction mixture, such as by applying a pressure of lessthan one atmosphere and/or a heated temperature of about 40 to about 60°C. The product may be purified to obtain a purity of about 50% to about95%, such as of about 90% to about 95%, as measured by area percentageHPLC.

The Ramelteon prepared by the process of the invention may be used fortreatment of insomnia. It can be combined with a pharmaceuticallyacceptable excipient to prepare pharmaceutical compositions.

Having described the invention with reference to certain preferredembodiments, other embodiments will become apparent to one skilled inthe art from consideration of the specification. The invention isfurther defined by reference to the following examples describing indetail the process and compositions of the invention. It will beapparent to those skilled in the art that many modifications, both tomaterials and methods, may be practiced without departing from the scopeof the invention.

EXAMPLES

All purity described in the examples is determined by HPLC.

Synthesis of Intermediate-IV Example I

A compound of formula IV was prepared by Witting-Horner reaction inwhich compound of formula II (100.0 gm, 0.6165 mol) was reacted withtriethyl phosphono acetate (276.21 gm, 1.2331 mol) in presence of 60%NaH (29.5 gm, 1.2331 mol) in toluene (1000 ml) under nitrogenatmosphere. Reaction was stirred for 18-24 hr at 85-95° C. undernitrogen atmosphere. Reaction progress was checked by TLC and HPLC. Thereaction mixture was cooled to room temperature (RT) and water was addedinto it after completion of reaction. The organic layer and aqueouslayer were separated. The aqueous layer was extracted with toluene andthen combined organic layer was washed with 10% brine solution.Distilled out the organic layer under vacuum at 45-50° C.

Yield: 65-70% Purity 92-95%.

NMR of compound IV

1.178-1.218 (t, 3H), 3.294 (s, 2H), 3.613 (s, 2H), 3.759 (s, 3H),4.070-4.141 (q, 2H), 6.462 (s, 1H), 6.754-6.790 (dd, 1H) 6.920-9.928 (s,1H), 7.330-7.357 (d, 1H).

Synthesis of Intermediate-V Example 2A

Compound of formula IV (100.0 gm, 0.4305 mol) was reduced in methanol(1500.0 ml) and water (300.0 ml) mixture in presence of 5% Pd/C (13.0gm) in hydrogen pressure. The reaction mixture was stirred for 2-3 hrsat RT and reaction progress was monitored by HPLC and TLC. The reactionmixture was filter on hyflow bed after completion of reaction. Distilledout solvent under reduce pressure at 45-50° C.

Yield: 92-95% Purity 92-95. %

NMR of compound V—1.178-1.218 (t, 3H), 3.294 (s, 2H), 3.613 (s, 2H),3.759 (s, 3H), 4.070-4.141 (q, 2H), 3.486-3.555 (pentate, 1H),4.415-4.456 (m, 2H), 6.754-6.790 (dd, 1H) 6.920-9.928 (s, 1H),7.330-7.357 (d, 1H).

Example 2B Chiral Reduction

Compound of formula IV (100.0 gm, 0.4305 mol) is reduced in methanol(500.0 ml) and toluene (500 ml) mixture in presence of[RuCl(benzene)((R)-BINAP)]Cl, under hydrogen pressure. The reactionmixture is stirred for 20-22 hr at 80-90° C. and reaction progress ismonitored by HPLC and TLC. After completion of reaction, the reactionmixture is filtered trough hyflow and Mixture of toluene and methanol isdistilled out under reduce pressure at 50-55° C.

Synthesis of Intermediate-VI Example 3

Compound of formula V (100.0 gm, 0.4304 mol) in methanol (1000.0 ml) wasstirred in presence of sodium acetate (38.8 gm, 0.4735 mol) for 5-10minute and then bromine (68.6 gm, 0.4304 mol) was added drop wise intoit at 0-5° C. The reaction mixture was stirred for 2-3 hrs at 0-5° C.Sodium bisulphite solution was added after completion of reaction andstir reaction mass for 5-10 min and then distilled out methanol underreduce pressure at 45-50° C. MDC (methylene dichloride) was added afterdistillation. The organic layer was separated and washed it with 5%sodium bisulphite solution. MDC layer was distilled out under reducepressure at 40-45° C.

Yield: 90-92%; Purity: 92-97%

NMR of Compound VI

1.258-1.305 (t, 3H), 1.721-1.837 (m, 1H), 2.332-2.460 (m, 2H),2.676-2.928 (m, 3H), 3.492-3.587 (pentate, 1H), 3.859-3.890 (s, 3H),4.146-4.217 (q, 2H), 6.763 (s, 1H), 7.376 (s, 1H).

Synthesis of Intermediate-VII Example 4

A mixture of compound of formula VI (100.0 gm, 0.3192 mol) indichloromethane (1500 ml) was cooled at −25 to −30° C. BBr₃ (159.9 gm,0.6385 mol) was added dropwise into reaction mixture at −25 to −30° C.The reaction mixture was stirred for 3-4 hrs at −25 to −30° C. Reactionprogress was checked by TLC and HPLC. Reaction mixture was poured intochilled water with stirring. The layers were separated. The organiclayer was washed with 10% brine solution. Distilled out dichloromethanelayer and obtained product as a liquid which was solidified. Yield:80-85%; Purity by area percentage by HPLC: 95-98%.

NMR of Compound VII

1.259-1.355 (t, 3H), 1.689-1.808 (m, 1H), 2.322-2.455 (m, 2H),2.672-2.856 (m, 4H), 3.461-3.557 (pentate, 1H), 4.148-4.218 (q, 2H),6.843 (s, 1H), 7.290 (s, 1H).

Synthesis of Intermediate-IX Example 5

Added Compound VII and 3-5 vol of Dimethyl formamide, 2.5 moleequivalent Sodium Hydride is added at −05 to 15° C. and stirred thereaction for 1-2 hr at −05 to 15°. Add Compound VIII lot wise and heatit to 80-95 temperature stir for 3-5 hrs, after completion of reactioncool the mass to 25-30 temperature, add acetic acid to adjust pHneutral, add Water 30-50 times to isolate product. Filter the slurry.Yield is 80%-85%. Purity 95-99%.

NMR data: 1.203-1.238 (t, 6H), 2.281-2.384 (m, 1H), 2.521-2.573 (q, 1H),2.742-2.829 (m, 2H), 3.523-3.559 (q, 1H), 3.942-4.012 (m, 2H),4.816-4.842 (m, 1H), 5.373 (s, 2H), 6.770 (s, 1H), 7.334 (s, 1H).

Synthesis of Intermediate-X Example 6

Compound of formula IX (100.0 gm, 0.2407 mol) is added to methanesulfonic acid (46.22, 0.4814 mol) in toluene (1000.0 ml) at 25-35° C.and the reaction mixture is stirred at 25-35° C. for 6-8 hr. Reactionprogress is monitored by HPLC and TLC, after completion of reaction,reaction mixture is poured into ice cold water. Separate organic andaqueous layers and organic layer is washed with water and brinesolution. Solvent is distilled off from organic layer to obtain thetitle compound.

Synthesis of Intermediate-XI Example 7

Compound of formula X (100.0 gm, 0.3094) is hydrogenated by 10% Pd/C(15.0 gm) in methanol (2000.0 ml) and water (200.0 ml). Reaction mixtureis stirred for 2-3 hrs at 25-30° C. under hydrogen atmosphere 5-10 kgpressure. Reaction is monitored by HPLC and TLC. After completion ofreaction, filter the reaction mixture on Hyflow and then solvent isdistilled off under reduced pressure at 45-50° C. to obtain the compoundof formula XI.

Synthesis of Intermediate-XII Example 8

A mixture of compound of formula XI (100.0 gm, 0.4059) in methanol(100.0 ml) and aqueous ammonia solution (500.0 ml) is stirred under for5-6 hr at 25-35° C. Progress of reaction is monitored by HPLC and TLC.Reaction mixture is poured into water and then extract twice with ethylacetate. Organic layer is washed with brine solution and then dried withsodium sulfate and organic layer is distilled off under reduced pressureat 45-50° C. The product is isolated.

Synthesis of Intermediate-XIII Example 9

The boron-trifluoride diethyl ether complex (350 ml, 277 mmol) is addedTHF 2500 ml) and cool it to −10-15° C. The sodium borohydride (104 gm,277 mmol) is added to reaction mixture and raise the temperature to25-35° C. and stir for 1-1.5 hr at 25-35° C. Again this liquid is cooledand compound of formula XII (100.0 gm, 460 mmol) is added. Afteraddition the reaction is stirred at 25-35° C. for 24-25 hr. The mixtureis concentrated under reduced pressure to yield solids, which aredissolved in ethyl acetate and treated with 1M hydrochloric acid. Themixture is concentrated to dryness and the resulting residue is washedwith diisopropyl ether to afford the hydrochloride salt of compound offormula XIII.

Synthesis of Ramelteon (I) Example 10

The hydrochloride salt of compound of formula XIII (100.0 gm, 418 mmol)is suspended in the THF at 4000 ml, triethyl amine (116.0 ml, 836 mmol)is added and the reaction is cooled to 10° C. or less. Propionylchloride (74 ml, 836 mmol) is added dropwise followed by agitation at25-35° C. for 2-3 hrs. Then 1000 ml, of water is added and the THF isdistilled off under reduced pressure. It dissolved in ethyl acetate andwash twice with 10% brine solution. Dry the organic layer with sodiumsulfate, distill off under vacuum and product is isolated. Dry theproduct under vacuum.

1. A compound having the following structure:

wherein X is O-Alkyl or —NH₂.
 2. The compound of claim 1, wherein X isethoxy.
 3. The compound of claim 1, wherein the compound has a purity ofat least about 50% as measured by area percentage HPLC.
 4. A compoundhaving the following structure:

wherein X is O-Alkyl or —NH₂.
 5. The compound of claim 4, wherein X isethoxy.
 6. The compound of claim 4, wherein the compound has a purity ofat least about 50% as measured by area percentage HPLC.
 7. The compoundof claim 4, wherein the compound has (s) isomeric configuration.
 8. Acompound having the following structure:

Wherein X=O-Alkyl or —NH₂.
 9. The compound of claim 8, wherein X isethoxy.
 10. The compound of claim 8, wherein the compound has (s)isomeric configuration.
 11. The compound of claim 8, wherein thecompound has a purity of at least about 50% as measured by areapercentage HPLC.
 12. A compound having the following structure:

Wherein X=O-Alkyl or —NH₂.
 13. The compound of claim 12, wherein X isethoxy.
 14. The compound of claim 12, wherein the compound has (s)isomeric configuration.
 15. The compound of claim 12, wherein thecompound has a purity of at least about 50% as measured by areapercentage HPLC.
 16. A compound having the following structure

wherein X is O-Alkyl or —NH₂.
 17. The compound of claim 16, wherein X isethoxy.
 18. The compound of claim 16, wherein the compound has (s)isomeric configuration.
 19. The compound of claim 16, wherein thecompound has a purity of at least about 50% as measured by areapercentage HPLC.
 20. A process for producing Ramelteon intermediate offormula IV comprising combining compound of formula II with compound offormula III in the presence of base and organic solvent.

Wherein X=O-Alkyl or —NH₂.
 21. The process of claim 20, wherein X isethoxy.
 22. A process for preparing Ramelteon comprising preparing thecompound of Formula IV according to claim 20, and converting it toRamelteon.
 23. A process for preparing a Ramelteon intermediate offormula V, comprising reduction of compound of formula IV in presence ofRu-BINAP complex under hydrogen atmosphere in an organic solvent.

Wherein X=O-Alkyl or —NH₂.
 24. The process of claim 23, wherein X isethoxy.
 25. A process for preparing Ramelteon comprising preparingcompound of formula V according to claim 23, and converting it toRamelteon.
 26. A process for preparing a Ramelteon intermediate offormula VI, comprising reacting compound of formula V with brominatingagent in presence of an acid or alkaline salt of an acid.

Wherein X=O-Alkyl or —NH₂.
 27. The process of claim 26, wherein X isethoxy.
 28. A process for preparing Ramelteon comprising preparingcompound of Formula VI as described in claim 26 and converting it toRamelteon.
 29. A process for preparing a Ramelteon intermediate offormula VII, comprising removing protective group for the hydroxyl groupin compound of formula VI.

Wherein X=O-Alkyl or —NH₂.
 30. The process of claim 29, wherein X isethoxy.
 31. A process for preparing Ramelteon, comprising preparingcompound of formula VII as described in claim 29, and converting it toRamelteon.
 32. A process for preparing the Ramelteon intermediate offormula IX, comprising reacting compound of formula VII with compound offormula VIII in presence of a base to produce the compound of formulaIX:

Wherein X=O-Alkyl or —NH₂.
 33. The process of claim 32, wherein X isethoxy.
 34. A process for preparing Ramelteon comprising preparing thecompound of Formula IX as described in claim 32, and converting it toRamelteon.
 35. A process for preparing the compound of formula IXComprising: a) reacting the compound of formula II with compound offormula III to obtain compound of formula IV:

b) reduction of compound of formula IV to obtain compound of formula V:

c) combining compound of formula V with brominating agent to obtaincompound of formula VI:

d) demethylation of the compound of formula VI to obtain the compound offormula VII:

e) combining the compound of formula VII with compound of formula VIIIin presence of base to produce the compound of formula IX:

f) converting compound IX into Ramelteon; Wherein X=O-Alkyl or —NH₂.